Bone marrow microenvironment in myelodysplastic neoplasms: insights into pathogenesis, biomarkers, and therapeutic targets

Bahmani, Forouzan; Shayanmanesh, Maryam; Safari, Mahdi; Alaei, Amirarsalan; Yasaman Pouriafar; Rasti, Zahra; Zaker, Farhad; Rostami, Shahrbano; Damerchiloo, Fatemeh; Safa, Majid

doi:10.1186/s12935-025-03793-z

Table 3 Emerging therapeutic agents targeting BM microenvironment

From: Bone marrow microenvironment in myelodysplastic neoplasms: insights into pathogenesis, biomarkers, and therapeutic targets

Therapeutic category	Agent	Target	Clinical trial phase	Patients/test model	Clinical trial ID-refs.
Cytokine inhibitors	Luspatercept (ACE-536)	TGF-β	III-Completed FDA approved	Lower-risk MDS	NCT02631070 [243, 278]
	Luspatercept (ACE-536)	TGF-β	II-Ongoing	Very low, low, or intermediate-risk MDS	NCT04477850 [30] NCT05732961 [70] NCT05181592 [70] NCT05732961 [70] NCT06045689 [100] NCT05925504 [36]
	Luspatercept + Lenalidomide	TGF-β	I/II-Ongoing	Nondel(5q) MDS	NCT04539236 [50]
	Luspatercept Injection (Reblozyl) + Eprex	TGF-β	I/II-Ongoing	Lower-risk MDS without RS (Failed or Being Ineligible to ESA)	NCT05181735 [150]
	Roxadustat + Luspatercept	TGF-β	IV-Not yet recruiting	Refractory MDS-RS	NCT06006949 [62]
	Ker-050	TGF-β	II-Ongoing	Lower-risk MDS	NCT04419649
	Galunisertib	TGF-β R	II-Completed	Lower-risk MDS	NCT02008318 [248]
	Vactosertib + Fludarabine Phosphate + Cyclophosphamide + IL-2 + Natural Killer Cells	TGF-β R	I-Ongoing	MDS Other hematologic malignancies	NCT05400122 [12]
	Siltuximab	IL-6	II-Completed	Lower-risk MDS	NCT01513317 [249]
	Infliximab	TNF-α	II-Completed	Lower-risk MDS	NCT00074074 [253]
	Etanercept	TNF-α R	I/II-Completed	MDS	NCT00118287 NCT00217386 NCT00093366 NCT00005853
	BMS-986253	IL-8	I/II-Ongoing	MDS	NCT05148234
	Canakinumab	IL-1β	I-Completed	Very low-, low-, and intermediate- risk MDS	NCT04810611
	Canakinumab	IL-1β	II-Ongoing	Low- or intermediate-risk MDS CML	NCT04239157 [263]
	Canakinumab Injection + Darbepoetin Alfa	IL-1β	II- Ongoing	Lower-risk MDS	NCT04798339 [41]
Signaling pathway inhibitors	Tomaralimab (OPN-305)	TLR2	I/II-Completed	Lower-risk MDS (HMA failure)	NCT02363491 [254]
	CX-01	TLR2/4	I-Completed	R/R MDS AML	NCT02995655
	Emavusertib (CA-4948)	IRAK4	I/II-Ongoing	Higher-risk MDS R/R AML	NCT04278768 [153, 279]
	R289	IRAK1/4	Ib- Ongoing	Lower-risk MDS	NCT05308264 [34]
	Bortezomib	TRAF6	I/II-Completed	Lower-risk MDS (HMA failure)	NCT01891968 [280]
	Ibrutinib	ASC/NLRP3	I-Completed	Higher-risk MDS (Refused standard therapy)	NCT03359460 [259]
	Ibrutinib	ASC/NLRP3 Caspase-1	I-Ongoing	Higher-risk MDS (HMA failure) HMA-naive higher-risk MDS	NCT02553941 [260]
	DFV890	NLRP3	I-Ongoing	Very low-, low- or intermediate- risk MDS Lower risk CMML	NCT05552469 [80]
Immune checkpoint inhibitors	Sabatolimab	TIM-3	II-Ongoing	Lower-risk MDS	NCT04823624 [20, 281]
	Sabatolimab + Azacitidine + Decitabine	TIM-3	II-Ongoing	Higher-risk MDS	NCT04878432 [39]
	Sabatolimab + NIS793 + canakinumab	TIM-3	I-Completed	Lower-risk MDS	NCT04810611 [33]
	Sabatolimab + azacytidine + venetoclax	TIM-3	II-Ongoing	Higher-risk and very higher-risk MDS	NCT05020912 [281]
	Sabatolimab + HMAs	TIM-3	Ib-Completed	Higher-risk MDS AML	NCT03066648 [121]
	Sabatolimab + HMAs	TIM-3	II-Ongoing	Higher-risk MDS	NCT03946670 [121]
	Sabatolimab + azacytidine + Placebo	TIM-3	III-Ongoing	Higher-risk MDS	NCT04266301 [282]
	Ligufalimab (AK117)	CD47	I/II-Ongoing	MDS	NCT04900350 [283]
	Magrolimab + Azacitidine, Placebo + Azacitidine	CD47	III-Completed	MDS	NCT04313881 [269]
	Magrolimab + Azacitidine	CD47	Ib-Completed	MDS R/R AML	NCT03248479 [284, 285]
	Magrolimab + Decitabine/Cedazuridine	CD47	II-Completed	Intermediate-, high- or very high-risk MDS	NCT05835011 [100]
	IBI188 + Azacitidine	CD47	I-Ongoing	Higher-risk MDS	NCT04485065
	TQB2928 Injection + Azacitidine	CD47	I-Ongoing	MDS AML	NCT06008405
	ALX148 + Azacitidine	CD47	I/II-Ongoing	Higher-risk MDS	NCT04417517 [286]
	Pembrolizumab	PD-1	Ib-Completed	Lower- and higher-risk MDS (HMA failure)	NCT01953692 [121]
	Pembrolizumab + azacytidine	PD-1	II-Ongoing	HMA failure MDS	NCT03094637 [121]
	BI 836858	CD33	II-Completed	Low- and intermediate 1- risk MDS	NCT02240706 [287]
	Nivolumab and/or ipilimumab ± azacytidine	PD-1 (Nivo) CTLA-4 (Ipi)	II-Ongoing	HMA failure MDS	NCT02530463 [121]
	Nivolumab and ipilimumab ± azacytidine	PD-1 (Nivo) CTLA-4 (Ipi)	Basket exploratory phase II	HMA failure MDS	NCT02530463 [121]
Bi and Tri-specific antibodies	Flotetuzumab (MGD006)	CD3 + CD123	I/II-Completed	Intermediate- and higher- risk MDS AML	NCT02152956 [288]
	JNJ-67571244	CD3 + CD33	I-Completed	MDS AML	NCT03915379 [289]
	Vibecotamab	CD3 + CD123	II-Ongoing	MDS AML	NCT05285813 [290]
	AMV564	CD3 + CD33	I-Completed	Intermediate-2 and high-risk MDS	NCT03516591 [291]
	APVO436	CD3 + CD123	Ib-Ongoing	MDS AML	NCT03647800 [292]
	GTB-3550	CD16 + IL-15 + CD33	I/II-Completed	Higher-risk MDS R/R AML	NCT03214666 [293]
Chimeric Antigen Receptor (CAR) cells	CATCHAML (CAR-T cell)	CD123	I-Ongoing	AML/MDS	NCT04318678 [269]
	ARC-T (CAR-T cell)	CD123	I-Ongoing	Higher-risk MDS and AML	NCT05457010 [269]
	CLL1-CD33 cCAR- T-cell	CLL1 + CD33	I-Ongoing	Refractory higher-risk MDS	NCT03795779
	APVO436 (CAR-T cell)	CD123 + CD3	I-Ongoing	MDS AML	NCT03647800 [294]
	MP0533 (CAR-T cell)	CD33 + CD123 + CD70 + CD3	I/II-Ongoing	MDS AML	NCT05673057 [294]
	IPH6101/SAR443579 (CAR-T cell)	CD123 + CD16 + NKp46	I/II-Ongoing	MDS AML	NCT05086315 [294]
	NKX101 (CAR-NK cell)	NKG2D-Ls	I-Ongoing	Adult with MDS Adult with AML	NCT04623944 [61]
	CAR.70/IL15-transduced CB-NK cells (CAR-NK cell)	IL15-transduced	I-Ongoing	MDS and other hematologic malignancies	NCT05092451 [269]
Vaccines	TAA whole-cell vaccine (K562-GM-CSF-CD40L Vaccine) + lenalidomide + GM-CSF	TAA	I-Completed	Intermediate- and higher-risk MDS (Failed-HMA treatment)	NCT00840931 [266]
	TAA whole-cell vaccine (GVAX vaccine)	TAA	II-Completed	MDS, CMML, or AML	NCT01773395 [266]
	PR-1Peptide vaccine + Montanide + GM-CSF	Proteinase-3 + neutrophil elastase (PR-1)	I/II-Completed	MDS-RAEB	NCT00004918 [266]
	WT-1 peptide vaccine + montanide + GM-CSF	Wilms’ Tumor 1 (WT1) antigen	I-Completed	MDS Other hematologic maligncies	NCT00665002 [266]
	WT-1 and PR-1 Peptide vaccine + montanide + GM-CSF	Combined PR1 and WT1	I-Completed	Montanide + GM-CSF	NCT00313638 [266]
	RHAMM Peptide vaccine + Incomplete FreudAdjuvant + GM-CSF	The receptor for hyaluronic acid-mediated motility (RHAMM)	I/II-Completed	MDS Multiple myeloma	ISRCTN32763606 [266]
	DEC-205/NY-ESO-1 Fusion Peptide vaccine + Decitabine + Nivolumab	DEC-205/NY-ESO-1 fusion protein CDX-1401	I-Completed	Intermediate- and higher-risk MDS	NCT01834248 [266]
	NY-ESO-1, MAGE-A3, PRAME, WT-1 Peptide vaccine + Azacitidine	Long peptide sequences from NY-ESO-1, PRAME, MAGE-A3, WT-1	I-Completed	Higher-risk MDS	NCT02750995 [266]

HMA, hypomethylating agent; TGF-β: transforming growth factor beta; TGFBR1: TGF-β receptor 1; TNF-α: tumor necrosis factor α; TRAF: tumor necrosis factor receptor associated factor; CML: chronic myeloid leukemia; TLR: toll-like receptors; IRAK: interleukin-1 receptor-associated kinase; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; NLRP3: NLR family pyrin domain containing 3; R/R: refractory/relapsed; RS: ring sideroblast; PD-1: programmed death 1; CTLA-4: cytotoxic T-lymphocyte associated protein 4; TIM-3: T-cell immunoglobulin mucin-3; TAA: tumor associated antigen; Nivo: nivolumab; Ipi: ipilimumab; cCAR: compound chimeric antigen receptor; NKG2D: natural killer group 2; GM-CSF: granulocyte–macrophage colony-stimulating factor; CMML: chronic myelomonocytic leukemia; RAEB: refractory anemia with excess blasts

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